Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439

Mol Cancer Ther. 2018 Oct;17(10):2091-2099. doi: 10.1158/1535-7163.MCT-18-0038. Epub 2018 Jul 25.

Abstract

Targeting the PI3K pathway is a promising strategy for treating prostate cancers with PTEN-loss. However, current anti-PI3K therapies fail to show long lasting in vivo effects. We find that not only the PI3Kα- and PI3kβ-isoforms, but also PI3Kδ, are associated with the epithelial-mesenchymal transition (EMT), a critical process distinguishing indolent from aggressive prostate cancer. This suggests that cotargeting PI3Kα/β/δ could preempt the rebound activation of the parallel pathways induced by α- or β-isoform-selective inhibitor and prevent EMT. Indeed, BAY1082439, a new selective PI3Kα/β/δ inhibitor, is highly effective in vivo in inhibiting Pten-null prostate cancer growth and preventing EMT in the mutant Pten/Kras metastatic model. The anti-PI3Kδ property of BAY1082439 further blocks B-cell infiltration and lymphotoxin release, which are tumor microenvironment factors that promote castration-resistant growth. Together, our data suggest a new approach for the treatment of prostate cancer by targeting both tumor cells and tumor microenvironment with PI3Kα/β/δ inhibitor. Mol Cancer Ther; 17(10); 2091-9. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Disease Progression
  • Humans
  • Immunohistochemistry
  • Immunophenotyping
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Mice
  • PTEN Phosphohydrolase / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / immunology
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction / drug effects*
  • Tumor Microenvironment / drug effects*

Substances

  • Protein Kinase Inhibitors
  • Class Ia Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase